The endogenous cannabinoid system has been implicated in diverse biological processes as well as pathophysiologies including cachexia, obesity, dyslipidemia, nausea/vomiting, chronic pain, inflammation, drug dependence, neuropsychiatric disorders, multiple sclerosis, and cancer. The major guiding hypothesis of this project is that the complex physiological and pharmacological properties of the endocannabinoid system are due to both direct and indirect activation/inactivation of CB1, CB2 and as-yet-unidentified (CBx) receptors. To determine the contributions of each receptor/binding site to the physiological and pathological processes mediated by the endocannabinoid system, the proposed series of targeted experiments will evaluate the effects of receptor-selective ligands in animal models of specific disorders in which the endocannabinoid system has been implicated (e.g., substance abuse, psychiatric disorders, obesity and pain). Complementary in vitro studies will be used to verify selectivity of the ligands, as well as to investigate mechanisms involved in their in vivo effects. To date, most in vivo research has focused on delineation of cannabinoid effects mediated by orthosteric interaction with CB1 receptors. However, increasing evidence suggests that cannabinoid action at CB2 and CBx receptors, as well as allosteric modulation of CB1 receptors, may produce pharmacological profiles that are distinctly different from those produced by orthosteric CB1 agonists and antagonists. Hence, the proposed research will focus primarily on the effects of ligands that act via mechanisms other than the orthosteric site of the CB1 receptor. Aim 1 will focus on characterization of a novel class of 3-substituted pyrazole rimonabant analogs with in vivo effects mediated by non-CB1, non-CB2 mechanism(s). If these ligands activate a novel cannabinoid (CBx) receptor (as is hypothesized), delineation of their behavioral effects will not only determine potential therapeutic indications of the compounds, but also may suggest possible physiological roles of this receptor system. Aim 2 will examine the behavioral effects of CB2 receptor selective agonists in animal models of stimulant abuse and schizophrenia, disorders for which recent research has implicated CB2 receptor involvement. In Aim 3, allosteric modulators of the CB1 and CB2 receptors will be developed. Hypotheses to be examined in this aim are that allosteric modulators are likely to exhibit greater receptor selectivity and that they will have a side effect profile that lacks the marijuana-like intoxicatio effects of orthosteric CB1 receptor agonists. Whereas Aims 1-3 focus on the acute effects of cannabinoids, Aim 4 will examine the effects of sub-chronic administration, an important consideration since most therapeutic indications for which cannabinoids are being developed are chronic conditions. Increasing scientific knowledge of the contributory roles of different receptor mechanisms involved in endocannabinoid system functioning could enhance understanding and treatment of a wide variety of disorders in which dysregulation of the endocannabinoid system has been implicated, including substance abuse, psychiatric disorders, obesity, and various neurological disorders.